Thrombotic Microangiopathy Without Thrombocytopenia as a Manifestation of Hypertensive Emergency

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1.

Hypertensive emergency is defined as extremely high blood pressure, equal to or over 180 mmHg systolic pressure and 110 mmHg diastolic pressure coupled with evidence of end‐organ damage. Hypertensive emergency has an incidence rate of two new cases per one million people per year and results in a greater than 90% 1‐year mortality rate without treatment [1, 2]. The complete mechanism resulting in hypertensive emergency has not been elucidated. However, certain processes are thought to contribute to the pathogenesis, including the overactivation of the renin‐angiotensin aldosterone system (RAAS) [3]. Hypertensive emergencies are associated with a wide spectrum of resulting end organ damage, including thrombotic microangiopathy (TMA), which characteristically presents with thrombocytopenia. We present a case of hypertensive emergency resulting in TMA without thrombocytopenia.

A 58‐year‐old female patient with a history of coronary artery disease treated with coronary artery bypass graft, ischemic cardiomyopathy, hypertension, hyperlipidemia, insulin dependent Type 2 diabetes mellitus, and chronic anemia secondary to stage 2 chronic kidney disease, with a baseline hemoglobin of approximately 8.5 mg/dL, presented with shortness of breath for 4 days and worsening peripheral edema. Their echocardiogram 2 months prior to admission demonstrated a left ventricular ejection fraction of 49%, mild concentric hypertrophy, no valvular disease, and left ventricular diastolic dysfunction. The patient had no history of liver disease. The patient's blood pressure ran 146–204/77–112 mmHg on initial evaluations (Table 1). Chest x‐ray and B‐type natriuretic peptide of 2938 pg/mL indicated a fluid overloaded status. The patient was admitted and treated for acute hypoxemic respiratory failure secondary to acute on chronic heart failure exacerbation with 40 mg of furosemide twice a day, 50 mg of carvedilol twice a day, 10 mg of empagliflozin, 20 mg of lisinopril, and 25 mg of spironolactone daily along with bilevel positive airway pressure. On the second day of admission, the patient's hemoglobin dropped from 7.6 mg/dL to 6.9 mg/dL. Haptoglobin was undetectable, reticulocyte count was 8.4%, bilirubin was 2.0 mg/dL, and lactate dehydrogenase (LDH) was 523 U/L, all suggesting a hemolytic anemia pathology was underway. Prothrombin time (PT) was 12.2 s and activated partial thromboplastin time (aPTT) was 21.9 s. Creatinine was 1.11 mg/dL. On peripheral blood smear, 1–2 schistocytes per high powered field, burr cells, elliptocytes, hypochromia, macrocytic cells, and polychromasia were present. The Coombs direct antibody test was negative, and platelets were within normal limits (413 × 10⁹/L).

TABLE 1.

Blood pressure and laboratory marker trends over course of admission.

	Day 1 (admission)	Day 2	Day 3	Normal values
Systolic blood pressure/diastolic blood pressure (mmHg)	204/112	170/89	159/85	< 120/80
Platelets (109/L)	491	413	335	150–450
Hemoglobin (g/dL)	7.6	6.9	7.6–8	12.0–16.0
Total Bilirubin (mg/dL)	3.5	2.0	1.1	0.2–1.2
Haptoglobin (mg/dL)	—	Below assay limit	40	62–197
LDH (IU/L)	—	523	320	84–246
Creatinine (mg/dL)	1.11	1.31	1.63	0.50–1.30

Because of the patient's markedly increased blood pressure, a diagnosis of hypertensive emergency was considered, and the patient's lisinopril dose was increased to 40 mg a day. The next morning, after tightening blood pressure control, the patient's hemoglobin increased from 6.9 to 7.6 mg/dL, with one reading of 8 mg/dL, bilirubin improved from 2.0 to 1.1 mg/dL, and haptoglobin went from undetectable to 40 mg/dL. The patient was discharged with plans for outpatient follow‐up and labs in 1 week. The patient's hemoglobin remained stable around 7.5–7.6 mg/dL following this episode of hemolysis.

In the setting of markedly increased blood pressures and end‐organ damage manifesting as hemolytic anemia, the patient was deemed to have had a hypertensive emergency. The hemolysis laboratory markers' response to blood pressure control supports the hypertensive emergency etiology. Moreover, other cases of TMA associated with hypertensive emergency demonstrate resolving hemolysis once blood pressure control is achieved [4, 5].

Other etiologies for the patient's symptoms were considered. Hemolytic uremic syndrome (HUS) was less probable because of the lack of fever and gastrointestinal symptoms.

Thrombotic thrombocytopenic purpura (TTP) was also considered in the differential diagnosis. The patient's PLASMIC score was 5, placing them at an intermediate risk for TTP. Although ADAMSTS13 activity was not obtained and serves as a limitation of our case, the patient was not thrombocytopenic, had normal mental status, and demonstrated rapid improvement in hemolysis following blood pressure control alone without plasma exchange. In this setting, ADAMTS13 assays may aid in diagnostic clarification but are not definitive in isolation. Relative reductions in ADAMTS13 activity have been described in secondary TMAs, including those associated with hypertensive emergency, and do not necessarily indicate TTP [6, 7]. Importantly, ADAMTS13 assays often have prolonged turnaround times and should not delay the initiation of appropriate therapy when an alternative cause of TMA is strongly suspected.

Disseminated intravascular coagulation (DIC) was considered less likely given the absence of clinical triggers, normal coagulation parameters (PT and aPTT), and preserved platelet counts. The patient demonstrated marked reticulocytosis, elevated LDH, undetectable haptoglobin, indirect hyperbilirubinemia, and schistocytes on peripheral blood smear, all consistent with intravascular hemolysis due to microvascular red blood cell fragmentation. In contrast, DIC is primarily characterized by systemic activation of the coagulation cascade, which often manifests as abnormalities in coagulation studies and thrombocytopenia. While fibrinogen and D‐dimer can aid in the evaluation of DIC and would have provided additional supportive data, their absence does not outweigh the hemolysis‐predominant laboratory pattern observed in this case.

Moreover, the patient had no history of aortic stenosis or foreign body to create shearing. The patient was not on any medications known to lead to hemolytic anemia. Autoimmune hemolytic anemia was an uncompelling cause as a result of the negative Coombs direct antibody test. Therefore, the most compelling conclusion was a hypertensive emergency resulting in hemolytic anemia.

While the mechanism is not fully elucidated, hemolytic anemia associated with hypertensive emergency is thought to be associated with severe endothelial injury due to the extremely high blood pressure, leading to the formation of small vessel microthrombi [6]. This endothelial damage results in the release of von Willebrand factor (VWF) and a relative deficiency of ADAMTS13, a VWF‐cleaving protease, which contributes to the persistence of large VWF multimers and subsequent platelet aggregation and microthrombi formation [6]. Activation of the RAAS system promotes the expression of proinflammatory cytokines during hypertensive emergencies and contributes to further vascular damage and renal ischemia [3, 8].

Another proposed mechanism of TMA in the setting of hypertensive emergency involves abnormal complement levels and defective complement regulation. Complement‐activated TMA has been found to be associated with mutations of complement proteins, including the CFH, CFI, CD46, C3, CFB, CFH, CFP, PLG, and THBD genes [9]. Notably, 69% of patients with TMA secondary to hypertensive emergency confirmed by kidney biopsy were found to have significant ex vivo Cb59 formation, further highlighting the role of complement [10]. Clinicians should consider obtaining complement and screening for complement gene variants to aid in their confirmation of TMA as well as to evaluate for the potential utility of complement inhibitors.

An important mechanistic caveat is that this patient never presented with thrombocytopenia, a classic sign of TMA. However, there is evidence that TMA can occur without thrombocytopenia, as described in Cavero et al. in the context of HUS‐related TMA [11]. One retrospective cohort study of 967 patients with TMA found thrombocytopenia was only present in 40.3% of patients [12]. While precise incidence rates of TMA without thrombocytopenia in the context of hypertensive emergencies are not well established, from our literature search, it appears to be exceedingly rare.

Hypertensive emergencies require urgent and rapid treatment and can present with hemolytic anemia. The severity of thrombocytopenia in TMA can vary, and in some instances, platelet counts may remain within normal limits or be only mildly reduced. This variability can make diagnosis challenging. Nevertheless, due to the severe mortality associated without treatment, there must remain a high clinical suspicion for TMA in the absence of thrombocytopenia in the setting of hypertensive emergency.

Data Availability Statement

Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.